Klotho regulation and aging

Klotho 调节和衰老

• 批准号: 7770294
• 负责人: Gwendalyn DiAnn King
• 金额: $ 8.37万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7770294
• 关键词: 3' Untranslated Regions; Accounting; Affect; Age; Age-Months; Aging; Aging-Related Process; Animals; Atherosclerosis; Atrophic condition of skin; Binding; Binding Sites; Bone Density; Brain; Brain Injuries; Brain Part; Cell physiology; Cells; Cessation of life; Deterioration; Development; Disease; Down-Regulation; Elements; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genetic Translation; Guanine + Cytosine Composition; Hair; Human; Impaired cognition; Impairment; In Vitro; Infertility; Knowledge; Lead; Life; Light; Longevity; Macaca mulatta; Metabolism; MicroRNAs; Modeling; Molecular; Mus; Mutant Strains Mice; Neurodegenerative Disorders; Neurons; Normal Cell; Organ; Osteoporosis; Oxidative Stress; Pathway interactions; Phenotype; Population; Predisposition; Process; Proteins; Pulmonary Emphysema; Rattus; Reactive Oxygen Species; Regulation; Resistance; Rodent; Role; SP1 gene; Sampling; Signal Pathway; Time; Transcription Initiation; Transgenic Mice; Translations; Work; age effect; age group; age related; aged; aging brain; aging gene; aging population; anti aging; biological adaptation to stress; calcification; klotho protein; long term memory; mRNA Stability; memory retention; nonhuman primate; normal aging; novel; overexpression; oxidation; oxidative damage; pathological aging; prevent; promoter; public health relevance; response; therapeutic development; transcription factor

DESCRIPTION (provided by applicant): The focus of our study is to examine how the age suppressor protein, Klotho, is regulated with aging in the brain. When Klotho expression is eliminated, mice develop normally, but age to death by 4 months of age. This rapid deterioration is accompanied with a phenotype not unlike what is observed in aged humans (cognitive impairment, atherosclerosis, ectopic calcification, emphysema, osteoporosis, skin atrophy and hair loss, thymic involution, infertility and decreased bone mineral density). Elimination of Klotho in mice causes cognitive impairment that is associated with increased oxidative stress. In contrast, Klotho overexpressing transgenic mice live longer by up to 30% and are resistant to oxidative stress. Our group found that Klotho is downregulated in the aging non-human primate, rat and mouse brains Together, these have lead us to hypothesize that Klotho is important in brain function and its downregulation with age may be the result of oxidative stress which, if prevented, could ameliorate decline into neurodegenerative disease. The work proposed, examines regulation of the Klotho promoter and 3'UTR with age and the effect of oxidative damage to the Klotho promoter with age. We will determine whether the high GC content of the Klotho promoter makes it a target for age-related downregulation because of damage that accumulates over time because of oxidative stress. This will be done by comparing the oxidation state of the Klotho promoter to that of other genes both in vitro and in post mortem samples from aged rhesus monkey brain. We will also work to characterize the transcription factors that bind and induce activation of the Klotho promoter. The Klotho promoter does not contain the classical elements for transcription initiation. Understanding what factors are important for Klotho transcription may shed light on signaling pathways leading to Klotho activation and the role of Klotho in the normal cell. Last, we will determine whether Klotho is regulated by microRNAs (miR) and how miR change in the brain with age. MiR bind and regulate translation of mRNA and nothing is known about whether and how miR affect Klotho processing. Again, understanding the processes that regulate Klotho will enable us to have a better understanding of the processes that affect Klotho and Klotho's wider role in cellular function. The results of this work will add new knowledge on both the anti-aging gene Klotho and elucidate a possible mechanism for how oxidative damage selectively downregulates specific genes. PUBLIC HEALTH RELEVANCE: With a rapidly aging population, increases in age related disorders are anticipated to rise to unprecedented levels in the next 50 years. Understanding the regulation of genes known to effect and be affected by the aging process is critical to developing novel therapies for a range of disorders. The aging suppressor protein, Klotho is decreased in the brain with age and may be a target for therapeutic development against neurodegenerative disorders.

描述（由申请人提供）：我们研究的重点是检查年龄抑制蛋白Klotho如何随着大脑中的衰老而调节。当Klotho表达被消除时，小鼠正常发育，但在4个月大时衰老至死亡。这种快速恶化伴随着与在老年人中观察到的表型（认知障碍、动脉粥样硬化、异位钙化、肺气肿、骨质疏松症、皮肤萎缩和脱发、胸腺退化、不育和骨矿物质密度降低）相似的表型。在小鼠中消除Klotho会导致与氧化应激增加相关的认知障碍。相比之下，Klotho过表达转基因小鼠的寿命延长了30%，并且对氧化应激具有抵抗力。我们的小组发现Klotho在衰老的非人类灵长类动物、大鼠和小鼠大脑中下调，这些使我们假设Klotho在脑功能中很重要，其随年龄的下调可能是氧化应激的结果，如果预防，可以改善神经退行性疾病的衰退。这项工作提出，检查Klotho启动子和3'UTR随年龄的调节以及氧化损伤对Klotho启动子随年龄的影响。我们将确定Klotho启动子的高GC含量是否使其成为年龄相关下调的靶点，因为氧化应激会随着时间的推移而累积损伤。这将通过比较Klotho启动子与其他基因在体外和来自老年恒河猴脑的死后样品中的氧化状态来完成。我们还将努力表征结合并诱导Klotho启动子激活的转录因子。Klotho启动子不包含用于转录起始的经典元件。了解哪些因素对Klotho转录很重要，可能会揭示导致Klotho激活的信号通路以及Klotho在正常细胞中的作用。最后，我们将确定Klotho是否受microRNA（miR）的调控，以及miR在大脑中如何随年龄变化。miR结合并调节mRNA的翻译，并且关于miR是否以及如何影响Klotho加工还不清楚。再次，了解调节Klotho的过程将使我们能够更好地了解影响Klotho的过程以及Klotho在细胞功能中的更广泛作用。这项工作的结果将增加关于抗衰老基因Klotho的新知识，并阐明氧化损伤如何选择性下调特定基因的可能机制。 公共卫生关系：随着人口的迅速老龄化，预计在未来50年内，与年龄相关的疾病将上升到前所未有的水平。了解已知影响和受衰老过程影响的基因的调节对于开发一系列疾病的新疗法至关重要。衰老抑制蛋白Klotho在大脑中随着年龄的增长而减少，并且可能是针对神经退行性疾病的治疗开发的目标。